Sarcopenia, cachexia and aging: diagnosis, mechanisms and therapeutic options - a mini-review

Abstract

By the year 2050, individuals over the age of 65 years will comprise 20% of the US population. Loss of muscle mass and strength is common in this age group and it is associated with increased dependence, frailty and mortality. Sarcopenia, defined as the loss of muscle mass and function associated with aging, and cachexia, defined as weight loss due to an underlying illness, are muscle wasting disorders of particular relevance in the aging population, but they go largely unrecognized. In this review we highlight the common pathophysiological mechanisms underlying muscle loss in sarcopenia and cachexia, the factors unique to each condition and means of diagnosing and differentiating them clinically. Therapeutic options including exercise, nutritional therapy, androgens and growth hormone as well as their practical limitations are discussed. We also shed light on newer agents being developed as potential therapeutic options for wasting diseases.

Figure. 1. Simplified Cellular Pathways for Muscle Protein Synthesis and Degradation

Synthesis pathways are in blue. Proteolytic pathways are in red. The dotted lines represent pathways that are not well characterized. Anabolic signals activate the PI-3 Kinase/Akt/mTOR pathway resulting in protein synthesis. Inactivity and inflammatory cytokines result in activation of NF-κB and Fox-O mediated induction of genes resulting in muscle atrophy. Fox-O activates transcription of ubiquitin proteasome ligases resulting in protein degradation. PI3-Kinase/AKT phosphorylates Fox-O preventing its nuclear translocation and inhibiting its activity. Fox-O when active can inhibit the mTOR pathway. Also, mTOR pathway activation inhibits protein degradation by lysosomal caspases. Myostatin causes muscle atrophy, via activating Fox-O and inhibiting PI3-K. IGF-1= insulin like growth factor 1, BCAA= branched chain amino acids, PI3-K= phosphoinositol 3 kinase, mTOR= mammalian target of rapamycin, NF-κB= nuclear transcription factor kappa B. Fox-O= transcription factor forkhead O

Figure 2. Pathophysiology of sarcopenia

GH= growth hormone, IGF-1= insulin-like growth factor-1. *Immobility may also be considered part of disuse atrophy rather than sarcopenia

Figure 3. Pathophysiology of cachexia

Various disease- or treatment-related factors lead to inflammation, hypogonadism, anorexia and insulin resistance resulting in muscle and fat loss, anemia, and fatigue and ultimately leading to cachexia. These factors are interdependent and altered by disease type, stage and treatment. CRP= C reactive protein